a study to investigate safety, tolerability, and pk of oral doses of tck-276 in patients with rheumatoid arthritis

Conditions: Rheumatoid Arthritis

Summary: the study is to evaluate the safety, tolerability, and pharmacokinetic (pk) of multiple orally administered tck-276 in both males and females with rheumatoid arthritis (ra).

this is a phase 1, multi-center, double-blind, randomized, placebo-controlled, multiple ascending dose (mad) study. the study will consist of a screening visit (days -1 to day 10), treatment duration (up to 11 days) and a follow-up/end of treatment (eot) visit. this mad study will consist of 4 cohorts of 8 patients (6 active treatment and 2 matching placebo, or a 3:1 ratio), each receiving an oral dose of tck-276 or matching placebo for 7 days (once daily (qd) under fed condition). the first cohort will be divided into 2 subgroups to implement the sentinel dosing approach. the study duration is approximately 42 days.

Eligibility criteria:
inclusion criteria: * diagnosis of ra and meeting the 2010 american college of rheumatology/european league against rheumatism classification criteria for ra. * patients between the ages of 18 and 64 years, inclusive, at the screening visit. * female patient must be not pregnant, not breast feeding and one of the following conditions need to apply: 1. of non-childbearing potential based on documented surgical treatment or post-menopausal, meaning patient had spontaneous amenorrhea for at least 12 months without alternate medical cause prior to screening visit and follicle stimulating hormone (fsh) \> 40 u/ml at the screening visit. 2. of childbearing potential and using a highly effective method of contraception and agrees to remain on a highly effective method from the time of signing the informed consent form (icf) until 21 days after the last dose. * male patient must agree to stay abstinent or must use together with his female partner(s) a form of highly effective contraceptive (failure rate of \< 1% per year) from the time of signing the icf until up to 3 months after the last dose of the study drug. * nonsmokers (or other nicotine use) as determined by history and by negative urine cotinine concentration at the screening visit and at admission. * body mass index (bmi) between 18.5 and 32.0 kg/m2, inclusive, at the screening visit. * patient is required to have completed a covid-19 vaccine regimen within no more than 5 months prior to screening to be eligible for the study. * permitted concomitant medications for any reason, must be on a stable dose. * permitted medications include: anti-malarials; nonsteroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors at approved dosage, and low dose oral corticosteroids; methotrexate concomitantly with folic acid or folinic acid. exclusion criteria: * female patients who are breastfeeding or have a positive urine pregnancy test. * patients who are unable to eat the prescribed meals during the stay at the site; vegetarian or vegan. * patient has a history of significant drug allergy. * patient has used a study drug, any prohibited medication(s), over-the-counter (otc) medications, vitamins, dietary and herbal supplements. * patient has a history of active suicidal ideation, or any psychiatric disorders that will affect the patient's ability to participate in the study. * patient has a current or recent history of uncontrolled, clinically significant infectious, hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease. * patient with any of the laboratory abnormalities as per reference. * patient has a history of alcohol and/or drug abuse within 24 weeks. * patient has positive results for drug testing and breath alcohol test. * regular consumption of alcohol within 6 months prior to the screening visit. * patient has positive test for hepatitis b surface antigen (hbsag), anti-hepatitis b core (hbc) antibodies, hepatitis c virus (hcv) antibody, and/or human immunodeficiency virus (hiv) antibody at screening visit. * patient has qt interval corrected for heart rate (qtc) using fridericia's correction (qtcf) \> 450 ms for males or qtcf \> 470 ms for females either at the screening visit or admission, based on safety 12-lead electrocardiogram (ecg). patient has screening or admission ecg with second- or third-degree atrioventricular block, bundle branch block, arrhythmia (but not sinus arrhythmia or supraventricular premature beats), or illegible qt interval. * patient has history or evidence of cardiopathy, acute coronary syndrome, hypertrophic cardiomyopathy, myocarditis or qt prolongation syndrome. * patient is unwilling to abstain from drinks and foods containing alcohol, grapefruit, or caffeine * patient has donated blood or experienced acute blood loss (including plasmapheresis) of greater than 500 ml within 90 days prior to the first dose of study drug. * patients with a known immunodeficiency disorder. have a history of a major organ transplant or hematopoietic stem cell/marrow transplant. * patients with infections requiring treatment or hospitalization within 14 days prior to the screening visit, parenteral antimicrobial therapy within 60 days prior to the screening visit, infected joint prosthesis; history of herpes zoster, active herpes simplex, or herpes simplex on suppressive therapy. * patient has a chronic hepatic disease or hepatic impairment. * patient has a history of mycobacterium tuberculosis or positive interferon gamma release assay for tuberculosis (igra-tb) or abnormal chest x-ray (for positive igra-tb patients). * patient has a history of any lymphoproliferative disorder. * patient has a history of covid-19 unless fully recovered with no sequelae for 14 days. * patient who had a severe course of covid-19 (extracorporeal membrane oxygenation, mechanically ventilated). * patient who has recent exposure to someone who has covid-19 symptoms or positive test result. * patient who has a positive reverse transcription polymerase chain reaction (rt-pcr) test for severe acute respiratory syndrome corona virus 2 (sars-cov-2). * patient who has clinical signs and symptoms consistent with sars-cov-2 infection. * patients may not receive any live/attenuated vaccine from 30 days prior to the screening visit until day 14 follow-up visit. * covid-19 vaccine should not be given 1 week prior to the screening visit. * patients with malignancy or history of malignancy except adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ. previous treatment with total lymphoid irradiation. * history of recurrent inflammatory joint disease other than ra or history of any other autoimmune rheumatic diseases other than sjogren's syndrome. * major surgery within 30 days prior to the screening visit or patients with planned surgery. * patients who have an abnormal chest x-ray for interstitial lung disease (ild) and/or patients with history of ild. * history of fainting or family history of sudden death. * patient has any disorder that would interfere with the absorption, distribution, metabolism or excretion of study drug. * patient has a history of deep vein thrombosis and/or pulmonary embolism. * patient has poor venous access.

Keywords: multiple ascending dose autoimmune disease disease modifying antirheumatic drugs (dmard)